Benzodioxepine derivatives of guanidine

ABSTRACT

THE BENZODIOXEPINE DERIVATIVES OF GUANIDINE OF THE FORMULA IN WHICH M IS EQUAL TO 0 OR 1 AND R IS A MEMBER OF THE GROUP FORMED BY HYDROGEN AND THE HYDROXY RADICAL, AND THEIR ACID ADDITION SALTS, USEFUL AS HYPOTENSIVE AGENTS.   2H-1,5-BENZODIOXEPIN   7-(H2N-C(=NH)-NH-(CH2)M-CH(-R)-)-3,4-DIHYDRO-

United States Patent 066 3,651,089 Patented Mar. 21, 1972 US. Cl. 260-340.3 6 Claims ABSTRACT OF THE DISCLOSURE The benzodioxepine derivatives of guanidine of the formula in which m is equal to 0r 1 and R is a member of the group formed by hydrogen and the hydroxy radical, and their acid addition salts, useful as hypotensive agents.

This is a divisional application of SN. 617,463, filed Feb. 21, 1967, now Pat. N0. 3,502,695.

The present invention relates to new derivatives of guanidine, particularly heterocyclic compounds of guanidine, and also to the processes for the preparation thereof.

Certain derivatives of guanidine are known, these being particularly the [2-0ctahydro-l-azocinylethyl] guanidine sulphate, described by Maxwell and collaborators (Experentia, 15, 267 (1959)) and the (1,4-benzodioxan-2-yl) methyl guanidine sulphate, described by J. Augstein and collaborators (J. of the Medicinal Chemistry 8, 446, 1965). These derivatives have hypotensive properties.

The new compounds of the invention are formed by guanidine derivatives of amines of the noradrenaline type, of which the hydroxyl groups are blocked in a heterocyclic ring, such as the dioxepine ring.

They are represented'by the formula in which;

in is equal to O or 1;

X is a member of the group formed by hydrogen and the halogens;

and R is a member of the group formed by hydrogen and the hydroxy radical.

These guanidines can be prepared according to the invention by one or other of the following methods, which enable them to be obtained with satisfactory yields.

According to the first method, an amine base of the general formula in which X, R, and m have the same meanings as above,

is caused to react with a salt of S-alkyl isothiourea. The reaction preferably takes place under heat in a solvent.

According to the second method, the guanidines of the invention can be obtained by condensation of a salt of the above amine with cyanamide.

When X is a halogen in the general formula, it is possible to use a process which consists in halogenating a salt of a guanidine of formula /O O NH:

preferably in a solvent, such as acetic acid.

The guanidines in free form are easily prepared by treatment of the compounds, obtained by the preceding methods, with a concentrated alkali base, then the addition salts with the mineral and organic acids, starting with guanidines.

These addition salts are novel and as such form part of the invention.

When m=0, and R and X represent hydrogen in the general formula, the guanidines of the invention are prepared from amines of formula These amines are themselves obtained from nitriles of formula These compounds are novel and as such form part of the invention.

The nitriles of the invention are obtained by dehydrating the corresponding aldoxime, itself synthesized by condensation of the formyl benzodioxane or benzodioxepine with hydroxylamine. According to one method of carrying out the invention, acetic anhydride is used as dehydrating agent. By reduction of the nitrile the expected amines are obtained with a very Satisfactory yield. This reduction is preferably effected with lithium-aluminium hydride.

The 7 (2' amino-1'-ethanol)-3,4-dihydro-2H-benzo dioxepine-1,5 can be obtained according to the invention by reduction, using the first method, of the cyanhydrin of 7-formyl-3,4-dihydro-2H-benzodioxepine-1,5 or, using the second method, of the 7-(2-nitro-1'-ethanol)-3,4-dihydro- 2-benzodioxepine-1,5.

The guanidines of the invention, and also their addition salts with mineral and organic acids, show remarkable hypotensive properties. i

The activities of these compounds were determined by different methods. Tests were first of all carried out on an anesthesised rat, and the results of these tests are set out in column 1, 2 and 3 of the following table. The arterial pressure was recorded on a rat, dormant with urethane, and the action of the product on the hypertensions obtained by intravenous injection of =Noradrenaline and Tyramine were investigated. A first series .of tests was carried out by administering the product intravenously (I.V.) and investigating its action on the hypertensions obtained with the pressor amines [Noradrenaline (Nor) at Tyramine (Tyr)], themselves administered one hour afterwards. In a second series of tests, the animals were pretreated with the products to be tested, the day before the test with the pressor amines. These two tests permit the dissociation of the a-blocking efiects visible in the first test (columns 1 and 2), in acute form, and the more lasting efiects of the sympathoplegic type, visible with 4 in accordance with usual medical regimen by the use of tablets, pills encapsulations, aqueous suspensions, injectable solutions, syrups, elixirs and other suitable forms. An exemplary formulation of a tablet containing a dosage the pretreatment of the second test (column 3). unit quantity is as follows:

Tests were then carried out on an anesthesised cat, Mg. using the conventional connection of the nictitating Active compound membrane, and recorded before and after intravenous in- Lactose 79 jection of the product to be studied, the contractions ob- Cornstarch 12 tained by stimulation of the preganglionic fibre (column 10 Talc I 6 4 of the following table) of the post-ganglionic fibre Noyalgin 6 (column 5 of the table) and by injection of Adrenaline Starch (paste) 6 (column 6 of the table). The arterial pressure was simul- Magnesium stearate 1 taheously recorded The uanidino-6-meth l-1,4-benzodiox n ar 'cularl The tests set out in the column 7 of the following table in its h emisulphate form has a remarkibighyp dtensiv e were carried out on an active cat, the products being activity which was studied on human beings administered subcutaneously to active cats. During the It a found that the guanidino 6 methy1 14 benzo days l w the administration the Possible relaxation dioxane hemisulphate, in tablets each containing mg. of the mehtahhg membrane Y noted and the fraetlen of active principle and an excipient, administeredperorally of the eye q ye was determmed- 20 to invalids suifering from hypertension in a daily dose The toxicrtles of the compounds tested, set out in of 10 to 500 mg preferably 20 to 40 causes a reglk column 8 of thefable are expressed by the 50% letha1 lar lowering of the tension down to normal values. The h (1)14" 50) of the Products admlmstered administration of two tablets per day to invalids showlhtravenously a mouseing arterial hypertensions such as maxima at 22, 24,

The followmg table summarises the results of these 25 and minima at 14 11 15 on commencing treatment testsmakes it possible, after a treatment lasting 5 to 6 days,

NH to obtain a lowering of the hypertensions to maxima of 14 and minrma of 10 to 11. 1 EXAMPLE 1 0 7-(guanidino methyl)-3,4-dihydro-2H-benzodioxepine X 1,5-hemisulphate Tests on the anaesthetised rat Modification oi the hypertensive effects of Noradrenaline and Tyramine Product I.V. 1 hr. before Tests on the anaesthetised eat (nictitating membrane) Efiects of product in I.V. on-

Noradrena- Tyramine, Excitation oi- I Test DL line, percent on I.V. percent of of Product LP. the Pre-gangh- Pqst-gangh- Injected active mouse, inhibition inhibition previous day onic fibre omc fibre adrenaline cat rug/kg.

Products 1 2 3 4 5 6 7 8 R=H; m=0 13 29 POtBIEIi ZtiOII Nor. Inhibition 100%..- Inhibition 100%..- Potentiation Inactive.-- 17. 5

an yr. R=OH; m=1 0 5 No action No modification-.. No modification..- No modification do 25 Phentolamine 80 70 100 (methane sulphonate- Guanethidine. 40 Poteiti ation Nor. Inh1bit1on100% Inhibition 100%... P0tentiat1on-..... Aet1ve 20 an yr. 1

1 Potentiation of 110%.

The reading of this table shows that, for the majority of the compounds according to the invention, there is more or less strong inhibition of the hypertensive effects of Noradrenaline and Tyramine in the acute test on the rat (columns 1 and 2). It is a question of a sympathicolytic eflect of the same type as that of the products known under the name of phentolamine [(N-p-tolyl- N-m-hydroxyphenylaminoethyl)-imidazoline methane sulphonate]. It will be observed that for certain products, there is superimposed on the preceding action a sympathoplegic action of the same type as that of the product known under the name of Guanethidine [(2-octahydroazocinyl-l-ethyl)-guanidine sulphonate] with, in particular, inhibition of the contracting effects of the excitation of the pre-ganglionic and post-ganglionic fibres and, on the contrary, potentiation of the contracting effect of the injection of adrenaline in the study of the nictitating membrane on the anesthesised cat.

The compounds of this invention are readily compounded into pharmaceutical forms suitable for convenient administration to combat hypertension in invalids subject thereto. Dosages, ordinarily sufiicient to eifect the desired therapeutic result, range from about 10 mg. to about 500 mg. a day. These dosages are readily supplied N o- CH NHh NH -H S0 (0.

(a) Preparation of the 7-(aminomethyl)-3,4-dihydro-2H benzodioxepine-1,5

CH NHz voluminous precipitate is obtained, into which is introduced 50 g. of ice and a stream of CO for a period of 2 hours. The aldoxime is extracted with ether with a yield of 93 This compound is used in the crude state for the following operations.

18 g. of aldoxime are placed in solution in 30 ml. of acetic anhydride and refluxed for 30 minutes. After cooling, the solution is emptied on to 100 g. of crushed ice and the precipitate which forms is filtered suction which precipitate, recrystallised from a mixture of benzene and hexane, melts at 82 C.

An analytic sample recrystallised from hot water is in the form of pearly platelets, melting at 86 C. (sealed tube).

The yield of 7-nitrile-3,4-dihydro-ZH-benzodioxepine- 1,5 is 10.5 g., i.e. 64.5%.

Gravimelric analysis.-Calcd. for C I-I N0 mol. wt.=175.18 (percent): C, 68.55; H, 5.17; N, 7.99. Found (percent): C, 68.68; H, 5.01; N, 7.82.

1.4 g. (0.08 mol) of this nitrile are placed in solution in 100 ml. of dioxane and introduced at 0 C. into a suspension of 3.8 g. (0.096 mol) of AlLiH; in 250 ml. of anhydrous ether. I

After this addition, the mixture is stirred for 3 hours at 40 C. and then, after cooling on an ice bath, there are successively added 10 ml. of water, then 10 ml. of 20% NaOH, followed by ml. of water. Heating then takes place for 1 hour at 40 C. I

The precipitate is filtered by suction, the filtrate being evaporated and rectified. 56% of 7-(aminomethyl)-3,4- dihydro-ZH-benzodioxepine-1,5 are obtained, the boiling point of which is 118120 C./ 0.65 millibars.

The corresponding hydrochloride melts at 275 C. (sealed tube) and is sublimed in the region of 215 C.

Gravimetrz'c analysis.-Calcd. for C H NO -HClmol. wt.=215.67 (percent): C, 55.68; H, 6.54; N, 6.49. Found (percent): C, 55.59; H, 6.43; N, 6.36.

(b) Preparation of the 7-(guanidino methyl) -3,4-dihydro- 2H-benzodioxepine-1,5-hemisulphate EXAMPLE 2 7-(2'-guanidino ethyl)-3,4-dihydro-2H-benzodioxepine- 1,5-hemisulph-ate 3.86 g. (0.02 mol) of 7-(2-aminoethyl)-3,4-dihydro-2H- benzodioxepine-1,5 (Masaao Tomita-Yakagaku Zasshi 77, 1041-2, 1957) (the author does not specify the boiling point found to be 128 C./0.6 millibars) in solution in ml. of ethanol and 2.78 g. (0.02 mol) of S-methyl isothiourea in solution in 10 ml. of water, are refluxed for 4 hours.

After return to ambient temperature, a first batch crystallises (1.8 g.). After filtration by suction, the mother liquors have added thereto one volume of ethanol and then one volume of ether, these causing the precipitation of a second batch of 2.2 g. After being recrystallised twice from boiling water, 2.8 g. of brilliant flake are obtained which melt at 225 C. in a sealed tube (Gallen Kamp apparatus Gravimetric anlysis.--Calcd. for C H N O Smol. wt. 568.64 (percent): C, 50.69; H, 6.38; N, 14.78. Found (percent): C, 50.84; H, 6.20; N, 14.64.

EXAMPLE 3 7- (2'-guanidino-1'-ethanol)-3 ,4-dihydro-2H-benzodioxepinel ,S-hemisulphate NH CH-CHzNH--NH2, HzSO; (in

(a) Preparation of the 7-(2'-amino-1'-ethanol)-3,4- dihydro-ZH-benzodioxepine-1,5

First method.The cyanhydrin of the 7-formyl-2,4- dihydro-ZH-benzodioxepine-1,5, which will then be reduced, was prepared in the following manner:

Into 53.6 g. (0.19 mol) of bisulphitic salt of 7-formyl- 3,4-dihydro-ZH-benzodioxepine-1,5, dissolved in ml. of water, there are introduced 55.9 g. (1.14 mol) of NaCN in solution in cc. of water, while stirring and at a temperature of +5 C. After the addition, stirring is continued for 2 hours at this temperature and then for 1 hour at 25 C. The crude cyanhydrin extracted with the ether is obtained in the form of an orange oil with a yield of 89%.

Into 9.7 g. (0.24 mol) of AlLiH; and 340 ml. of anyhdrous ether, there are introduced at 10 C. and 45 minutes, 34.7 g. (0.17 mol) of previously obtained cyanhydrin in solution in 170 ml. of ethanol.

After stirring for 3 hours at ambient temperature, heating under reflux takes place for 4 hours. The substance is cooled and 34 ml. of water, 54 m1. of 20% sodium hydroxide and then 68 ml. of water are successively added, keeping the temperature at about 0 C.

The amine is extracted from this suspension with hot chloroform and, after drying, it is precipitated with hexane. The product obtained is filtered by suction, and is recrystallized from benzene. M.P.= C. Yield 12 g.

The boiling point of this amine is from 170 C./ 0.5 millibar.

Gravimetric analysis.Calcd. for C H NO -mol. wt.=209.24 (percent): C, 63.13; H, 7.25; N, 6.70. Found (percent): C, 63.03; H, 7.40; N, 6.72.

Second method.To 17.8 g. (0.01 mol) of 7-formyl- 3,4-dihydro-2H-benzodioxepine-1,5, 15.25 g. (0.25 mol) of nitromethane and 400 ml. of methanol, there is added while stirring at 8 C. a solution of 2.0 g. (0.1 at./g.) of sodium in 80 ml. of anhydrous methanol.

Stirring takes place for another 5 minutes at 10 C. and the pH value is adjusted to about 5 with 18 g. of CH COOH. The substance is left standing for 5 hours at 0 C. and the solvents are evaporated in vacuo in order to obtain the 7-(2'-nitro-1-ethanol) 3,4 dihydro-ZH- benzodioxepine-1,5, which is taken up in ether, dried over Na SO in order to give after evaporation of ether an oily compound which is reduced without purification with AlLiH using the procedure of the first method.

After rectification, there is obtained the 7-aminoethanol-3,4-dihydro 2H benzodioxepine-l,5, of which the melting point is 130 C. (benzene).

7 (b) Preparation of the 7-(2'-guanidino-1'-ethanol)-3,4- dihydro-2H-benzodioxepine-1,5 hemisulphate 4.18 g. (0.02 mol) of amine obtained according 'to (a) in solution in 42 ml. of ethanol and 2.78 g. (0.02 mol) of S-methyl isothiourea hemisulphate in 8 ml. of Water are refluxed for 4 hours.

The solution is allowed to crystallize, after return to ambient temperature, into a compound which, after recrystallization from boiling water, melts at 230-232" C. (sealed tube).

Gravimetric analysis. Calcd. for C ,H N O S'mol wt.==600.62 (percent): C, 47.99; H, 6.04; N, 14.00. :Found (percent): C, 48.07; H, 6.20; N, 13.88.

What we claim is:

1. A substituted guanidine of the formula:

in which m is equal to 0 or 1, and R is a member of the group consisting of hydrogen and the hydroxy radical.

3,247,221 4/ 1966 Augstein et a1. 260340.3 3,306,913 2/1967 "-Aug stein et a1. 260-340.3

ALEX MAZEL, Primary Examiner I. H. TURNIPSEED, Assistant Examiner V UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,651,0 9 D d March 21, 1972 Inventor) Darius MOIHO et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

NH Column 2, line 10 (in the formula) change C NHZ to read 0 Column 6, line 62, change "2.0" to read --2.3--

Signed and sealed this 29th day of August 1972.

( SEAL) Attest:

EDI-IAHD M.FLETGHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents FORM Po-1o50 (10-69) uscoMM-oc 60376-P69 US. GOVERNMENT PRINTING OFFICE: I969 0-366-33 

